Lactoferrin for Iron Regulation

Overseen By Abbie E. Smith-Ryan, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: University of North Carolina, Chapel Hill

Must not be taking: Antibiotics, Oral contraceptives

Disqualifiers: Anemia, Diabetes, Immunocompromised, others

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to assess how recombinant bovine lactoferrin, a protein in cow's milk, affects iron levels, gut health, and immune function in healthy adults. Researchers will compare it to a similar cow's milk supplement and a placebo. The study suits active men and women aged 18-42 who do not have anemia or allergies to common foods like milk and eggs and maintain regular exercise routines. Participants will visit the research site six times over 14 weeks for tests and supplements. As an unphased trial, this study allows participants to contribute to foundational research that could lead to new health insights.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are using oral contraceptives with iron supplementation or are currently on antibiotics, you may not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that recombinant bovine lactoferrin (rbLf) is generally safe for humans and animals. Studies on a similar product, recombinant human lactoferrin, found no harmful effects, even at high doses. Animal tests revealed no significant toxic effects.

Health authorities, such as the European Food Safety Authority, consider bovine milk-derived lactoferrin safe. It is widely used and approved for various purposes. Some sources indicate that consuming lactoferrin from cow's milk is likely safe for up to a year.

Overall, both recombinant and cow's milk-derived lactoferrin have demonstrated good safety in past studies, suggesting they are well-tolerated in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using recombinant bovine lactoferrin (rbLf) for iron regulation because it offers a unique approach compared to traditional iron supplements, which can sometimes cause gastrointestinal side effects. Unlike standard treatments that typically involve direct iron supplementation, rbLf is a protein that naturally helps regulate iron absorption and distribution in the body, potentially leading to a gentler and more balanced iron management. Additionally, bovine milk-derived lactoferrin (cmdLf) provides an alternative source of lactoferrin that could offer similar benefits, giving researchers a broader understanding of how different forms of lactoferrin might improve iron regulation. These innovative treatments aim to enhance iron metabolism with fewer side effects, making them promising options for better health outcomes.

What evidence suggests that this trial's treatments could be effective for iron regulation?

This trial will evaluate the effects of recombinant bovine lactoferrin (rbLf) and bovine milk-derived lactoferrin on iron regulation. Studies have shown that rbLf helps manage iron levels by interacting with proteins that control iron balance. Research suggests that rbLf may improve iron indicators, such as hemoglobin and serum iron, more effectively than some common iron supplements. Lactoferrin from cow's milk has been found to increase iron absorption, especially in infants, and boost overall iron levels. Additionally, lactoferrin enhances immune function by disrupting harmful bacteria. Both rbLf and lactoferrin from cow's milk show promise for improving iron management and immune health. Participants in this trial will receive either rbLf or bovine milk-derived lactoferrin, depending on their assigned treatment arm. ^{1 5 6 7 8}

Who Is on the Research Team?

Abbie Smith-Ryan, PhD

Principal Investigator

University of North Carolina, Chapel Hill

Are You a Good Fit for This Trial?

This trial is for healthy adults interested in how rbLf affects iron regulation, gut health, and immune function. Participants must be willing to undergo blood tests, take supplements daily for 4 weeks, and complete treadmill exercise tests. Those with anemia or unable to commit to the study schedule are excluded.

Inclusion Criteria

Body mass index less than 35 kg/m^2

Active: meeting American College of Sports Medicine exercise guidelines or exercising more than 2 days per week

My hemoglobin levels are within the normal range.

Exclusion Criteria

I have a diagnosis of Irritable Bowel Disease, Crohn's, or Celiac.

I have chronic eczema or asthma.

Vegan (due to supplement ingredients)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Run-in

Participants undergo a 2-week run-in period before starting treatment

2 weeks

1 visit (in-person)

Treatment Phase 1

Participants receive their first assigned supplement (rbLf, cmdLf, or placebo) for 4 weeks

4 weeks

2 visits (in-person)

Washout

Participants undergo a 2-week washout period between treatments

2 weeks

1 visit (in-person)

Treatment Phase 2

Participants receive their second assigned supplement (rbLf, cmdLf, or placebo) for 4 weeks

4 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Recombinant Bovine Lactoferrin

Trial Overview The study compares the effects of a recombinant Bovine Lactoferrin supplement (rbLf), cow's milk-derived Lactoferrin (bLf), and a placebo on iron levels and red blood cell capacity in men and women through regular supplementation followed by exercise testing over 14 weeks.

How Is the Trial Designed?

Group I: Females: Recombinant Bovine Lactoferrin (rbLf), then Bovine milk derived Lactoferrin Experimental Treatment 2 Interventions

After a 2-week run-in period, this arm will begin treatment with recombinant bovine lactoferrin for 4 weeks and following a 2-week washout start bovine milk derived lactoferrin for 4 weeks.

Group II: Females: Bovine milk derived lactoferrin (cmdLf), then Recombinant bovine lactoferrin Active Control 2 Interventions

After a 2-week run-in period, this arm will begin treatment with bovine milk derived lactoferrin and then following a 2-week washout start recombinant bovine lactoferrin for 4 weeks.

Group III: Males: Recombinant Bovine Lactoferrin (rbLf), then placebo Active Control 2 Interventions

After a 2-week run-in period, this arm will begin treatment with recombinant bovine lactoferrin for 4 weeks and following a 2-week washout start placebo for 4 weeks.

Group IV: Males: Placebo, then recombinant bovine lactoferrin (rbLf) Placebo Group 2 Interventions

After a 2-week run-in period, this arm will begin treatment with placebo for 4 weeks and following a 2-week washout start recombinant bovine lactoferrin for 4 weeks.

Recombinant Bovine Lactoferrin is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Lactoferrin for:

• Dietary supplement for iron regulation and immune function

Approved in European Union as Lactoferrin for:

• Dietary supplement for iron regulation and immune function

Approved in Canada as Lactoferrin for:

• Dietary supplement for iron regulation and immune function

Approved in Japan as Lactoferrin for:

• Dietary supplement for iron regulation and immune function

Who Is Running the Clinical Trial?

University of North Carolina, Chapel Hill

Lead Sponsor

Trials

1,588

Recruited

4,364,000+

TurtleTree Labs Inc

Collaborator

Trials

1

Recruited

110+

Published Research Related to This Trial

Recombinant bovine lactoferrin (rbLf) was successfully produced with a yield of 15.3 mg/l and 90.3% purity, demonstrating its potential for further research in antimicrobial applications.

Both recombinant rbLf and its pepsin-digested peptides showed significant antibacterial activity, with effectiveness rates of 79.8% and 86.9%, respectively, indicating their potential as immunomodulators.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression and characterization of recombinant bovine lactoferrin in E. coli. García-Montoya, I., González-Chávez, SA., Salazar-Martínez, J., et al.[2013]

Both human and bovine lactoferrins show strong interactions with specific lectins, indicating their potential roles in immune response and microbial recognition due to their glycosylation patterns.

The study highlights that while both types of lactoferrins can bind to various lectins, their binding properties differ, suggesting that human lactoferrins may have unique bioactive sites that could influence their therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recognition roles of the carbohydrate glycotopes of human and bovine lactoferrins in lectin-N-glycan interactions. Yen, MH., Wu, AM., Yang, Z., et al.[2016]

Commercially available bovine lactoferrin (CbLF) can mimic some of the beneficial effects of human lactoferrin (hLF) in infant formula, as it can resist digestion and bind to intestinal cells similarly to hLF.

CbLF promotes cell proliferation and differentiation, and enhances the expression of important immune factors, suggesting it could provide health benefits similar to those of breast milk when added to infant formula.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bovine lactoferrin can be taken up by the human intestinal lactoferrin receptor and exert bioactivities. Lönnerdal, B., Jiang, R., Du, X.[2022]

Lactoferrin is a powerful glycoprotein that plays a crucial role in the body's defense against infections and inflammation, primarily through its ability to bind iron and interact with various microbial components and cell receptors.

Research into lactoferrin's structure and function is ongoing, with potential applications in healthcare, including the development of recombinant human lactoferrin for therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structure and biological actions of lactoferrin. Nuijens, JH., van Berkel, PH., Schanbacher, FL.[2019]

In a study involving SD rats with iron deficiency anemia, treatment with iron saturated recombinant human lactoferrin (Fe-rhLf) significantly improved hemoglobin levels and red blood cell counts compared to the control group, indicating its efficacy in treating this condition.

The high dose of Fe-rhLf not only enhanced hematological parameters but also altered liver hepcidin and ferroportin expression, suggesting a mechanism of action that may involve regulation of iron metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of iron saturated recombinant human lactoferrin on alleviating iron deficiency anemia in rats]. Fang, YH., Feng, X., Xu, H., et al.[2019]

Lactoferrin, an iron-binding glycoprotein found in milk and other fluids, plays a crucial role in iron uptake in the intestines and acts as a bacteriostatic agent by limiting iron availability to bacteria.

Beyond its iron-binding capabilities, lactoferrin is also involved in immune responses and may function as a growth factor and bactericidal agent, highlighting its diverse biological significance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lactoferrin: molecular structure and biological function. Lönnerdal, B., Iyer, S.[2022]

Lactoferrin is a multifunctional glycoprotein with antibacterial, antiviral, anticancer, and immunomodulatory properties, making it a promising candidate for various clinical applications.

Advancements in genetic engineering have enabled the high-yield production of recombinant lactoferrin, which retains its biological activity and could enhance its use in medical treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Research progress in physicochemical characteristics of lactoferrin and its recombinant expression systems. Pang, XN., Hong, X., Wei, X., et al.[2017]

Bovine lactoferrin (bLF) significantly stimulates the proliferation of human peripheral blood mononuclear cells (PBMC) in a dose-dependent manner, indicating its potential as an immunomodulatory agent.

Only colostral bLF was found to induce the production of proinflammatory cytokines TNF-α and IL-6, particularly at a concentration of 50 µg/mL, suggesting that the source and iron content of bLF can influence its immunological effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bovine lactoferrin enhances proliferation of human peripheral blood lymphocytes and induces cytokine production in whole blood cultures. Zaczyńska, E., Kocięba, M., Śliwińska, E., et al.[2018]

A study on the oral toxicity of recombinant human lactoferrin (rhLF) in Wistar rats showed no significant toxic effects after 13 weeks of daily administration at doses up to 2000 mg/kg body weight.

The findings suggest that the no-observed-adverse-effect level (NOAEL) for rhLF is at least 2000 mg/kg/day, indicating a strong safety profile for this substance when consumed orally.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sub-chronic (13-week) oral toxicity study in rats with recombinant human lactoferrin produced in the milk of transgenic cows. Appel, MJ., van Veen, HA., Vietsch, H., et al.[2011]

Bovine Lactoferrin (bLf) at a low concentration (0.8 μM) significantly reduces biofilm production in Listeria isolates, which is important for preventing foodborne illnesses.

bLf enhances the effectiveness of antibiotics like oxytetracycline and streptomycin against E. coli, and ampicillin against Listeria, indicating its potential as a synergistic agent in combating antibiotic-resistant bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bovine Lactoferrin can Decrease the In Vitro Biofilm Production and Show Synergy with Antibiotics Against Listeria and Escherichia coli Isolates. García-Borjas, KA., Ceballos-Olvera, I., Luna-Castro, S., et al.[2021]

Dietary lactoferrin, now available from bovine sources and recombinant technology, has shown potential antibacterial and antiviral effects in the intestine, possibly enhancing immune function through a unique receptor-mediated pathway.

Lactoferrin may improve iron status in infants and pregnant women, stimulate intestinal cell growth, and even inhibit cancer development, suggesting it could be beneficial for infection prevention, inflammation reduction, and overall health in vulnerable populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nutritional roles of lactoferrin. Lönnerdal, B.[2019]

The study successfully produced recombinant human lactoferrin (rhLf) using a recombinant virus in BmN cells, resulting in a biologically active protein with a molecular mass of approximately 78 kDa.

This method allows for efficient production of rhLf, which could have various applications in medicine and nutrition due to its multifunctional properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant functional human lactoferrin expressed in baculovirus system. Liu, T., Zhang, YZ., Wu, XF.[2019]

In a study involving 100 weanling SD rats over 28 days, recombinant human lactoferrin (rhLF) showed no significant differences in food safety indicators compared to bovine lactoferrin (bLF), indicating that both are safe for consumption.

Both rhLF and bLF groups demonstrated improved serum iron levels and transferrin saturation compared to the control group, suggesting that these lactoferrins can enhance iron nutrition without adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Animal experiment of recombinant human lactoferrin based on the 28 days repeated oral toxicity]. Ma, B., Yuan, X., Wang, X., et al.[2019]

Recombinant human lactoferrin (rhLF) was successfully produced in the milk of transgenic cattle at concentrations of grams per liter, demonstrating a viable method for large-scale biopharmaceutical production.

Both natural human lactoferrin and rhLF exhibited similar iron-binding properties and effectiveness in fighting infections in various mouse models, indicating that rhLF can serve as a functional substitute for natural hLF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Large scale production of recombinant human lactoferrin in the milk of transgenic cows. van Berkel, PH., Welling, MM., Geerts, M., et al.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10825996/

The effectiveness of oral bovine lactoferrin compared to ... Data demonstrate that lactoferrin may be a modulating agent in iron homeostasis by targeting the IL-6, Hepcidin, Ferroportin interplay [8].

2. sciencedirect.com sciencedirect.com/science/article/pii/S2214799324000894

Bovine lactoferrin and its potential use as a functional ... Lactoferrin supplementation resulted in superior increases in iron status markers in comparison to ferrous sulphate supplementation. Interestingly, fractional ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7551115/

Lactoferrin from Bovine Milk: A Protective Companion for Life Results of this study demonstrated that significant increases in total body iron content and iron absorption in the intestine were observed only in infants fed ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04435574

Lactoferrin for Treatment of Iron Deficiency Anemia. Many studies showed that oral bovine lactoferrin for pregnant women increased levels of hemoglobin, total serum iron, and ferritin and decreased ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0899900714003451

influence of bovine lactoferrin from iron-fortified formula Our data indicated that the formula fortified with bLF positively affected the Hb and iron status of infants who were exclusively breastfed. The effects of bLF ...

6. fda.gov fda.gov/files/food/published/GRAS-Notice-GRN-669-Part-1.pdf

GRAS Notice (GRN) No. 669, Cow's milk-derived lactoferrin Batch Data of Synlait Milk-derived Bovine Lactoferrin ... concluded to be safe and GRAS based on absorption, distribution, metabolism,.

7. sciencedirect.com sciencedirect.com/science/article/pii/S027869152400293X

A review of the safety evidence on recombinant human ... Overall, results from animal and human studies showed that rhLF was well tolerated and safe. Animal data showed no significant toxicity-related outcomes.

8. webmd.com webmd.com/vitamins/ai/ingredientmono-49/lactoferrin

Lactoferrin - Uses, Side Effects, and More Consuming higher amounts of lactoferrin from cow's milk is possibly safe for up to one year. Human lactoferrin that is made from specially processed rice ...